This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The detrimental long-term sequelae of persistent HCV infection now comprise the leading indication for liver transplantation in the United States. Defining the elements of the immune response that fail or are insufficient to mediate HCV infection resolution in the majority of those infected is critical for advancing our understanding of how to therapeutically intervene in HCV disease pathogenesis and is the focus of our work. We have aimed to characterize phenotypic and functional differences of HCV-specific T cells with a focus on co-inhibitory molecules such as PD-1, a member of the B7 family of molecules. This work recently resulted in a publication showing an exhausted phenotype with high PD-1 expression on liver infiltrating HCV-specific lymphocytes in patients chronically infected with HCV. Access to a chronically infected patient cohort in whom liver biopsy tissue is available represents a great resource for studies characterizing the role of co-inhibitory molecules in HCV pathogenesis. We have now been able to extend our cohort to include patients undergoing liver transplant for HCV related liver failure. We obtain large wedge samples of donor and recipient liver for ex vivo analysis and have now, because of this cohort, been able to extend our studies to the intrahepatic antigen presenting cells responsible for stimulating the anti-HCV response. Functional studies of the T cells show enhanced proliferative capacity with blockade of the PD-1/PD-L1 interaction. However, these HCV specific T cells undergo massive apoptosis during HCV infection. Interestingly, in the acute phase of infection the HCV specific T cells also express the costimulatory molecule CD86 but rapidly lose expression with the transition to viral persistence. These data suggest that the interplay between costimulatory and coinhibitory molecules may be critical for immune control of viremia and provide further support and excitement for the forthcoming therapeutic studies.